Tuesday, August 10, 2010

Circles of SAM-E

Figuring out biochemistry is rather like watching a group of kids playing on the playground. Lots of kids bounce off each other, swing from jungle gyms for no apparent reason, and toss balls around. In the end, energy was consumed and fun was had.

One of the ball-carriers in our livers and brain is the vitamin co-factor SAM-E (pronounced "Sammy"). Otherwise known as S-Adenosyl methionine, SAM-E has a cute little sulfur moiety on it (the "S") that can carry around biochemical balls known as methyl groups (-CH3). You're probably really excited to learn that carrying around methyl groups is an extremely important job, and SAM-E is the go-to running back, the Earl Campbell or the pre-marijuana Ricky Williams of the vitamin crew.

SAM-E is important in depression because, along with folate, B6, and B12, it helps create three of the major neurotransmitters from their dietary amino acids - dopamine, norepinephrine, and serotonin. We can make SAM-E, but without enough essential vitamins (including B6 and B12) and the amino acid methionine, we can't make enough of it or recycle it. And studies have shown that people with depression tend to have lower serum levels of SAM-E.

A new study and editorial about SAM-E came out in this month's Green Journal (the American Journal of Psychiatry - which I'm embarrassed to say I can never remember the proper name of because we always call it the Green Journal). The research team is from the Mass General - George Papakostas, David Mischoulon, Jonathan Alpert, and Maurizio Fava. Full disclosure, back (a while ago!) when I was a chief resident, I had the opportunity to sit in on their weekly research meetings. They were doing some initial planning about SAM-E, but at the time they were mostly focused on the STAR-D trial. They were always pleasant, professional, and would toss brilliant ideas back and forth - it was quite invigorating just to be in the room, though we were all stuffed into a small space for the amount of people, with research assistants sitting on tables on the perimeter, and several of the key players (Alpert or Mischoulon) doing the same, if they arrived late!

Anyway, this current study, "SAMe Augmentation of Serotonin Reuptake Inhibitors for Antidepressant Nonresponders With Major Depressive Disorder. A Double-Blind, Randomized Clinical Trial" is pretty similar to drug industry trials of pharmaceuticals, though it was funded by an NIH grant, and the SAM-E and matching placebo were freely provided by Pharmavite (who makes SAM-E, I assume). They used healthy depressed adults with no history of bipolar disorder, no risk of getting pregnant during the trial, no psychosis, and no substance abuse who were already taking antidepressants. This is an augmentation trial - as we know from every antidepressant study in history and STAR-D (Sequential Treatment of Resistant Depression), antidepressants (no matter what variety) help about 30% of people feel pretty normal, 30% of people feel a bit better, and 40% of people feel the same or worse. SAM-E has a bunch of trials (between the IV and oral trials, I think I count 20!) showing it has similar efficacy to antidepressants, mostly tricyclics. Because SAM-E has a different mechanism than the standard antidepressants, it's important to see how the two might work together. Alone, they are all pretty "meh" unless you are in the lucky 30%. Together, you might start to approximate the body and brain environment that we would have with the types of stress, exercise, and nutrition for which we were evolved, without the excess inflammation and autoimmune reactions that cause depression in the first place... sigh. (I think these trials are interesting because they tell us a bit about the biochemistry of depression. And medicines can help! I've seen it many times. But if we don't find and address the possible dietary and environmental and psychological causes, adding medication can be a bit like pissing into the wind, if you pardon the expression. Just like with diabetes.)

In this preliminary study of 73 already-depressed on antidepressants individuals, the SAM-E augmented the effect pretty well, and without side effects, for the most part (most common ones are upset stomach and diarrhea, like any vitamin). SAM-E (dosed at 800mg twice daily by the end of the study) dropped the Hamilton D depression score by 10 points from baseline, while the placebo-treated group dropped only 6 points. I know that doesn't sound too exciting - but there are only a few FDA-approved medications for the treatment of resistant depression, and they can have some pretty horrible side effects, and they didn't work as well as SAM-E did in this particular study. There are reasons that it is not quite fair to compare the studies of other medicines to this SAM-E study, and they are all duly discussed in the editorial (which appears to be free online and linked above!).

Sweet! Take a vitamin (basically) and boost your antidepressant! SAM-E has also had some studies showing that it can protect the liver and reduce joint pain in arthritis. Win-win! What are the down sides?

Well, like any antidepressant worth its salt, SAM-E can cause mania and anxiety. In fact, I would feel remiss in recommending that anyone start it without at least talking about it with their doctor or therapist, and having a family member watch for signs of mania. Theoretically, if you take SAM-E and you don't take enough of the co-factors, you can end up with a lot of homocysteine lying around. Homocysteine is a marker for heart disease, but that doesn't stop some articles I read from suggesting that SAM-E could increase your risk of heart disease by increasing homocysteine if you don't take a multivitamin with it. (SIGH. Correlation does not equal... ah, never mind). I would be more concerned that it wouldn't work as well without the necessary vitamin cofactors - so take a multi with it! Also, it's expensive. The 800 mg twice a day dose would cost $111 dollars a month at this national chain (though some people might be able to get away with lower doses). For that, you could get a prescription antidepressant and a couple of visits to a therapist covered by insurance. Also, like any over the counter supplement, "buyer beware." Some of them are sold by milligram weight rather than by milligram dose - you wouldn't want to spend big bucks for half the amount you thought you were getting! In 2000, early tests of SAM-E products by an independent laboratory showed that half of the products had less SAM-E than claimed. By 2007, it seems the companies cleaned up their act, and testing of 11 brands showed they were what they claimed to be.

And, of course, no one knows the long term side effects of piling on SAM-E.

Better that we avoid all this in the first place by having an all-star vitamin football team from your terrific, organic and local grown, grassfed and pastured all natural foods diet and a clean, anti-inflammatory playing field from childhood. But sometimes the works are already a bit gunked up. We have some professional cleaning solutions, though those have some down sides, it may not be as much of a down side as leaving the works gunked up.


  1. great post! funny you mention mania..
    when i played around with SAMe a few months ago i used 2x400mg/day (morning/evening) together with several other of my favorite brain and mood boosters (NADH, Ginseng, ALC, etc), and during the first few days, had the most remarkable "bliss-flashs" you can imagine. imagine the most profound feeling of happiness and "everything is perfect" one could ever have. made my cry for like half a hour each time out of pure relieve, gratefulness and "ah, that's how life is supposed to feel!". unfortunately, those flashes only lasted for like 2 hours each, and went away completely after a few days of taking SAMe. now, if i occasionally take another 400mg SAMe, i only feel a slight uplift and maybe slightly more outgoing (i would consider myself a sub-clinically depressed INTP with several food intolerances and some typical symptoms of CFS). do you have any information on why tis positive effect of SAMe may only last for a few days/weeks? i had the impression that it probably just cleaned up a pending lack of methylation in my system and once the usual level was reached, there was "nothing more to do" for it so to say *g* now i'm checking out Pyridoxal-5-Phosphate (B6) since yesterday. also seems to have a pronunced "booster", and slight anti-depressant effect - very similar to ginseng - at least so far.

  2. Hi qualia. It's very common for antidepressant boosters to work for a maximum of 6 weeks then poop out. Cytomel, abilify, another antidepressant... doesn't matter what it is or what it does. May be placebo effect (which is thought to work through opiate mechanisms). No one knows.

  3. it absolutely amazes me how everything comes together in the brain. everything is needed for everything else. it's like one wrong ork in the road sets off a massive down spiral. i really need to read up more on the brain. i think its even more fascinating than nutrition and metabolism

  4. yes, unfortunately (pooping out). i guess the brain has very strong self-regulatory mechanisms and set-points that it tries to keep, no matter what (drug) tries to influence it. which is a good thing under normal/healthy circumstances i guess (like for overcoming emotional traumas etc).
    btw, have you, by chance, listened to the last podcast from NeuroScene? the interviewee basically states that the alleged link of serotonin to depression has now pretty much been proven to be complete BS. check it out: http://is.gd/edqEv
    and i would agree. serotonin has more of a calming, damping and relaxing effect on me (and also increases stress tolerance to a certain degree), but not necessarily an explicit anti-depressant one. so far, SAMe was the substance that came closest to my best case scenario of creating a strong "positive outlook to life" feeling that also felt completely natural and authentic (which is certainly NOT the case for any serotonin booster)

  5. Much cooler layout - very post-post-modern.

    Like it - and the content.

  6. Hi qualia - there are so many personalized reactions to targeting different neurotransmitters, and each medicine has its own complicated story - SSRIs are hardly selective for serotonin, for example. In general, though, I think:

    low serotonin = anger, aggression, suicidality. (may be related to hihg kyurnetic also)

    low dopamine/norepinephrine (hard to separate the two as norepi stimulates dopamine) = low motivation, low energy, poor focus, depressed mood

    GABA = anxiety and mood stabilization effects

    Oversimplified, as is everything!

    Thanks Leonrover. I hate white on dark, really, but I did like the brown...

  7. no, i think this "simplification" makes sense, heh. so, then, what would you say in your experience is the most effective way (naturally, or via medication) to boost dopamine/norepinephrine? methylphenidate? i now believe in my case it has a lot to do with a defective gut flora and digestion - maybe even celiac - which can indirectly create a ton of problems with the brain as well (leaky gut, leaky blood-brain barrier, exorphins, food intolerances, chronic inflammation, auto immunity, nutritional deficiencies, etc etc) <- i have all of that, and see huge differences in how my brain works and feels depending on how my digestion works, and how strict i watch my diet (mainly avoiding gluten and dairy), but i'm still in the middle of the process of fine-tuning everything.

  8. Hi qualia - I would have to say the recommendations are very personalized. For some it would be to maximize restorative sleep, for some behavioral strategies for organization, for some an SNRI, for some a stimulant, for some paradoxically a dopamine blocker. Many of my tools are sledgehammers, though, ones I'd rather not wield in the brain if there were a better choice.

  9. Can you recommend some readings on behavioral strategies for organization? Thanks.

  10. I have heard through the internet grapevine that only an undermethylated (one with elevated levels of histamine (and that's something that there is an actual blood test for) person will have relief of depression from SAM e. Also, in my very unscientific research, the overmethylated person will have mania from SAM e, but not an undermethylated, any treuth to this? Also antidepressants can induce mania even more scary than SAMe, because at least SAMe cycles out of your system much quicker than ADs.

  11. I started Sam-e about a week ago and as of this date, I'm having intense out-of-proportion anger at just about everything in life. It's pretty miserable. I'm taking 200mg in the morning and 100mg at night, I think I'm going to take that way down to maybe just 50mg in the morning for a week or so and see what that does. I really dislike being so angry!

    1. I started SAM-e about a week and a half ago. For the first few days I thought it was working great in fact someone said why are you like this? meaning social, friendly... After about two days, l became even more angry and hateful of people. I am totally dead inside and don't feel anything at all but anger and hate. what did you do and what were the results. did you stop taking the SAM e? what were the results. thanks

  12. If I am already taking an SSRI, an SNRI, and gabapentin, am I just chasing after the wind to hope that SAM-e is going to be the magic chemical ticket to happiness? This is a serious post by the way. I've been taking antidepressants since I was 14 and am now 25 and it was great at first and now I hate it and it only seems to be getting worse with age. I don't think I had a chemical imbalance as a teenager but I definitely do now.


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